This proposal deals with fundamental problems of human blood coagulation using a combined protein, enzyme and organic chemical approach. Specifically, its thrust is directed toward the following subjects. I. Elucidation of the molecular details of the pathways of activation of Factor XIII, including the newly recognized thrombin-independent pathway. Particular emphasis will be given to the regulatory role of fibrinogen on the thrombin-dependent pathway. II. Kinetic and mechanistic studies on Factor XIIIa. III. Novel procedures for the labelling and isolation of cross-linking sites of native protein substrates of Factor XIIIa and of related transamidating enzymes. IV. The rheological as well as thrombolytic evaluation of specific inhibitors of fibrin cross-linking. V. Comparative studies regarding the role and control of transamidating enzymes in clotting.